Fig. 3.

200 Primary bone diffuse large B-cell lymphoA Pleomorphic B cells with large irregular multilobulated nuclei and prominent nucleoli. B Crush and smear artefacts
are frequently observed in primary bone diffuse large B-cell lymphoma. C Extensive immunoreactivity for CD20, a pan-B-cell marker, in tumour cells of this primary bone diffuse
large B-cell lymphoma.

that primary bone DLBCL probably arises from centrocytes.
Naive B cells in the bone may enter lymphoid follicles as part
of an inflammatory/immu no logical resp onse and un dergo IGH
somatic hypermutation to become centrocytes in the germinal
centre light zone {1847}. Primary bone DLBCL may originate
from these centrocytes. Alternatively, the centrocytes from
which the lymphoma originates may also derive from extraos-
seous lymphoid tissue, migrate to the bone, and give rise to
lymphoma {1847}.
Macroscopic appearance
It is uncommon to see gross specimens of primary bone lym-
phomas, because diagnosis is made on biopsy material and
treatment consists of chemotherapy and radiotherapy without
surgery. If available, macroscopy shows a greyish-white and
fleshy tumour in the bone, frequently with areas of necrosis.
Histopathology
The majority (> of primary bone lymphomas are diffuse
large B-cell lymphomas. Follicular lymphoma, marginal zone
lymphoma, lymphoblastic lymphoma, Hodgkin lymphoma,
ALK-positive and ALK-negative anaplastic large lymphomas,
and other B-cell and T-cell lymphomas only rarely originate pri-
marily within the bone {1646,2103}.
DLBCL is characterized by a diffuse growth pattern of
large atypical lymphoid cells filling the marrow space, some-
times with prominent fibrosis. Bony trabeculae show reac-
tive changes. Neoplastic cells have large, round or irregular
nuclei, often with a cleaved or multilobated (or occasionally
pleomorphic) appearanee and variably prominent nueleoli.
Cytoplasm may be amphophilic but is not abundant. Crush
artefact is comm on; this histological finding should raise
the possibility of a lymphoma. Typically the tumour cells are
accompanied in areas by many reactive, non-neoplastic lym-
phocytes and histiocytes. The crush artefact, admixture of
reactive cells, and reactive bone may obscure the neoplastic
population, sometimes necessitating rebiopsy to obtain diag-
nostic tissue.
The rare cases of lymphoblastic lymphoma, ALK-positive and
ALK-n egative an aplastic large cell lymphomas (ALCLs), Burkitt
lymphoma, low-grade B-cell lymphomas, and other peripheral
T-cell lymphomas have pathological features similar to those
seen in extraosseous sites. ALCL in bone is very rare, but it is the
most comm on primary T-cell lymphoma of bone. Tumour cells
are large, with characteristic irregular, eccentric kidney-shaped
n uelei. Un commonly, classic Hodgki n lymphoma prese ntswith
bony invoIvement, probably reflecting extranodal localization of
a primary no dal Hodgki n lymphoma in most cases, although

Fig.3.201 Primary bone diffuse large B-cell lymphoma. A Extensive sclerosis with crush artefact in a case of primary bone diffuse large B-cell lymphoma mimicking sar-
coma. B PAX5 immunoreactivity highlights the spindle cell appearance of the neoplastic B cells.

490 Bone tumours

rare cases of classic Hodgkin lymphoma primary in bone are
described {2393}.
Immunohistochemistry
The diagnostic work-up for primary lymphomas of bone
includes a combi nation of light microscopy and a panel of
immunohistochemical markers as used to evaluate other lym-
phoproliferative disorders. Most primary bone lymphomas are
DLBCLs that express CD20, PAX5, and CD79a {617}. Optimally,
an immunohistochemical panel to evaluate cases thought to be
DLBCL includes CD20, PAX5, CD3, CD5, CD10, BCL6, BCL2,
IRF4 (MUM1), MYC, and Ki-67, as well as in situ hybridization for
EBV using EBV-encoded small RNA (EBER). Selected markers
may be added in cases with unusual features. With this panel,
primary bone DLBCL can be further subdivided into germinal-
centre B-cell (GCB) type and non-GCB type using BCL6,
CD10, and IRF4 (MUM1) immunohistochemistry (the Hans algo-
rithm) {73}: CD10+ or CD10-, BCL6+, IRF4 (MUM1)- supports
GCB type, whereas CD10-, BCL6- or CD10-, BCL6+, IRF4
(MUM1)+ supports non-GCB type. Non-GCB type suggests an
inferior prog nosis {2663}. ALCLs are diffusely positive for CD30
and are usually positive for at least one pan -T-cell marker such
as CD3, CD2, CD4, or CD5. In cases with an ALKtranslocation,
expression of ALK protein is observed (ALK-positive ALCL).
Cytology
Not clinically releva nt
Diagnostic molecular pathology
Clonal rearrangements of immunoglobulin heavy and light chain
genes are detectable in primary bone DLBCL, whereas clonal
rearrangement of the T-cell receptor genes are detectable in
T-cell lymphomas. In primary bone DLBCL, BCL2translocation
was found in approximately of cases, BCL6 transloca-
tion in and MYC translocation in 10%. High-grade B-cell
lymphomas with MYC and BCL2 and/or BCL6 rearrangements
(double-hit lymphomas) {3011} primary in bone are rare {1861}.
Recently, the genomic Iandscape of DLBCL has been evalu-
ated by extensive next-generation sequencing studies in large
cohorts of B-cell lymphomas, identifying frequent driver muta-
tions in genes such as MYD88, CD79A/CD79B, CARD11,
and TP53 that are associated with an adverse prog nosis and
resista nee to therapy {2588}, although such studies focusi ng
on primary lymphoma of bone are limited. In parallel with the
recommendation for performing triple (BCL2IBCL6IMYC) FISH
in DLBCL, it is likely that a targeted next-generation sequencing
approach will become part of the routine DLBCL diagnostics in
the near future, in order to better characterize the lymphomas
and tailor therapeutic choices {3196}.
Essential and desirable diagnostic criteria
Essential: lymphoma identified by histology and immunohisto-
chemistry; only bone affected, with no previous or concurrent
extraosseous disease except in regional lymph no des.
Staging
Not clinically relevant
Prognosis and prediction
Primary bone DLBCLs have a favourable prognosis. With
current treatment protocols (chemotherapy followed by radio-
therapy), overall survival is excellent {1360). Age is a significant
factor associated with survival, with age > 60 years indicative
of inferior survival {1361}. In general, GCB-type primary bone
DLBCLs are associated with a better survival than the non-GCB
type {1847}.
Bone tumours 491
Langerhans cell histiocytosis
Definition
Langerhans cell histiocytosis (LCH) is a clonal neoplastic pro-
liferation of myeloid dendritic cells expressing a Langerhans
cell (LC) phenotype. LCH can be unifocal or multifocal within
a single system (usually bone) or it can be multisystem {3078).
ICD-0 coding
9751/1 Langerhans cell histiocytosis NOS
9751/3 Langerhans cell histiocytosis, disseminated
ICD-11 coding
2B31.2 XH1J18 Langerhans cell histiocytosis
cell histiocytosis NOS
Related terminology
Not recommended: Langerhans cell granulomatosis.
Solitary lesion
Not recommended: histiocytosis X; eosinophilic granuloma.
Multiple lesions
Not recommended: Hand-Schuller-Christian disease.
Cases with disseminated or visceral involvement
Not recommended: Letterer-Siwe disease.
Subtype(s)
None
Localization
Single-system LCH predominantly invoIves the bone (skull,
femur, vertebrae, pelvis, ribs, and mandible) and less
comm only lymph node, skin, and lung. In multisystem LCH, the
skin, bone, liver, spleen, and bone marrow are prefere ntially
in volved.
Fig.3.202 Langerhans cell histiocytosis. A CT with a C2 vertebral lytic lesion of
Langerhans cell histiocytosis. B CT of the skull without contrast. Lytic lesion in the
right frontal bone with associated soft tissue component. Margins should be left intact
for proper healing in cases of bone Langerhans cell histiocytosis.
492 Bone tumours
Pileri SA
Cheuk W
Picarsic J
Langerhans
Fig. 3.203 Langerhans cell histiocytosis involving diaphysis of the left tibia. A Plain
X-ray shows a radiolucent lesion in the left tibia, with periosteal new bone forma-
tion. B In the same case, MRI shows an intramedullary lesion in the tibial diaphysis
with erosion of the adjacent cortex.
Clinical features
Signs and symptoms
Patients with single-system LCH are usually older children or
adults with a painful lytic lesion eroding the bone cortex. Solitary
lesions at other sites present as masses. Patients with multifocal
single-system LCH are usually you ng childre n with multiple or
sequential destructive bone lesions, often associated with adja-
cent soft tissue masses. Diabetes insipidus follows cranial bone
and parenchymal invoIvement. Patients with multisystem LCH
are infants presenting with fever, cytopenias, skin and bone
lesions, and hepatosplenomegaly {167,75}.
Epidemiology
The annual incidenee in children is about 5 cases per 1 mil-
lion population {1264}. The M:F ratio is 1.2:1 {75}. The annual
incidence in adults is 1-2 cases per 1 million population. The
disease is more cominon among individuals of European
descent and Hispanics. LCH can also be associated with Erd-
heim-Chester Disease, either con comita ntly or precedi ng, with
shared molecular alterations {901}.
Etiology
Unknown
Pathogenesis
The cell of origin is closer to a myeloid dendritic cell than to an
epidermal LC {74}. MAPK pathway activation plays a central role
in LCH pathogenesis {75}. A misguided myeloid differentiation
model has been proposed, in which activating MAPK muta-
tions at a pluripotent haematopoietic, tissue-restricted, or local
precursor level give rise to high-risk multisystem, multifocal
low-risk, or unifocal LCH, respectively {75}. These mutations,
Fig.3.204 Langerhans cell histiocytosis. A Low-power image of bone Langerhans cell histiocytosis with clusters of Langerhans cells and large numbers of eosinophils and
osteoclast-like giant cells. B High-power image of Langerhans cell histiocytosis showing distinctive morphology of intermediate-sized cells with nuclear grooves, irregular nuclear
contours, and pale eosinophilic cytoplasm.

especially BF?Z\F p.Val600Glu, may confer an advantage for tis-
sue site accumulati on via disrupted cell mi g rati on and apop-
tosis inhibition {1393}. Rare familial cases are reported {168}.
About of cases show clonal IGH, IGK, and/or TR gene
rearrangements {561}.
Macroscopic appearance
Not clin ically re leva nt
Histopathology
Diagnostic LCH cells are oval and measure about 10-15 pm.
They are recognized by grooved, folded, inden ted, or lobed
nuclei, as well as fine chromatin, inconspicuous nucleoli, and
thin nuclear membranes. Nuclear atypia is minimal, but mitotic
activity is variable and can be high without atypical forms. The
cytoplasm is moderately abundant, slightly eosinophilic, and
devoid of dendritic processes. The characteristic milieu includes
variable numbers of eosinophils, histiocytes (both multinucleated
LCH-type and osteoclast-type cells, especially in bone), neutro-
phils, and small lymphocytes. Plasma cells are usually sparse.
Occasionally, eosinophilic microabscesses with central necrosis
are found. LCH cells predominate in early lesions. In late lesions,
they are decreased in number, with increased foamy macro-
phages and fibrosis. The ultrastructural hallmark is the cytoplas-
mic Birbeck granule, which is 200-400 nm long and 33 nm wide,
with a tennis-racket shape and a zipper-like appearanee.
Immunohistochemistry
LCH cells express CD1a, CD207 (langerin), S100, CD68, and
HLA-DR {75}. CD45 expression is low. The BRAF p.Val600Glu
mutation can be identified by a specific antibody {2246,214}.
The Ki-67 proliferation index is highly variable (typically <
by double staining) {2511,1393}. Rare cases associated with fol-
licular lymphoma or B- or T-lymphoblastic leukaemia are con-
sidered a transdifferentiation phenomenon and behave more
aggressively {3274,981,512}.
Differential diagnosis
The differential diagnosis includes osteomyelitis and chondro-
blastoma.

Fig.3.205 Langerhans cell histiocytosis. A Langerhans cell histiocytosis with surface CD1a immunoreactivity on the majority of cells. B Langerhans cell histiocytosis with
cytoplasmic granular positivity for CD207 (langerin) in the majority of Langerhans cells. C Langerhans cell histiocytosis with molecularly confirmed BR/lFp.Val600Glu mutation
showing strong diffuse cytoplasmic granular VE1 positivity in Langerhans cells.

Bone tumours 493